Identification of the genetic mechanisms governing mammalian nephron endowment

鉴定控制哺乳动物肾单位禀赋的遗传机制

• 批准号: 10019324
• 负责人: Alison Jarmas
• 金额: $ 3.84万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-12 至 2023-09-11
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10019324
• 关键词: Address; Algorithms; Biological Assay; Cells; Childhood; Chromosomes; Chronic Kidney Failure; Clinical; Complement; Data; Development; Diagnostic; Embryo; Endowment; Environment; Epithelial; Epithelium; Equilibrium; Exhibits; Fellowship; Filtration; Fostering; Gene Expression Profile; Generations; Genes; Genetic; Genetic Determinism; Genotype; Human; Hybrids; Hypertension; Inbred Strain; Individual; Inner mitochondrial membrane; Intervention; Investigation; Kidney; Lecithin; Lipids; Lod Score; Mediating; Mesenchymal; Mesenchyme; Metanephric Diverticulum; Mitochondria; Modeling; Morphology; Mouse Strains; Mus; Mutation; Nephrology; Nephrons; Organogenesis; Outcome; Partner in relationship; Perinatal; Phenotype; Physicians; Population; Pregnancy; Premature Birth; Principal Investigator; Process; Quantitative Trait Loci; Renal Tissue; Renal function; Reporting; Research; Research Training; Respiration; Risk; Scientist; Series; Signal Transduction; Structure; System; TSC1 gene; Testing; Therapeutic; Tissues; Trees; Variant; WNT Signaling Pathway; burden of illness; cohort; conditional mutant; design; diagnostic screening; epithelial to mesenchymal transition; experimental study; genomic locus; mouse model; mutant; mutant mouse model; nephrogenesis; novel diagnostics; novel therapeutic intervention; offspring; postnatal; premature; prenatal; progenitor; programs; self-renewal; stem cells; therapeutic target; trait; treatment strategy

PROJECT SUMMARY & ABSTRACT Mammalian kidney function is critically dependent on the number of nephrons generated during renal development. Nephrons are the filtration unit of the renal system and arise from a nephron progenitor cell (NPC) population at the periphery of the developing tissue. NPCs interact with the surrounding ureteric bud (UB) and stromal compartments, balancing self-renewal and differentiation into segmented nephron structures via a mesenchymal-to-epithelial transition. Consequently, nephron endowment is a quantitative outcome determined by several processes including UB branching and NPC dynamics. Two noteworthy aspects of mammalian renal development are: (1) a 10-fold variation in nephron number (NN) between human kidneys from different individuals, ranging from 200,000 to >2.5 million units per kidney and (2) the synchronous depletion of remaining progenitors at postnatal day 3 in mice (gestational week 34-37 in humans). These facts pose compelling research questions, as the genetic contributions to these aspects of renal organogenesis are not currently known. From a clinical standpoint, a low nephron endowment, which is particularly prevalent in premature birth cohorts, contributes to high blood pressure and chronic kidney disease (CKD). These conditions pose an immense disease burden worldwide, particularly as there is no known postnatal generation of new nephrons. While various genetic and perinatal factors are demonstrated to reduce NN, there remains a clear need to identify genetic contributions to the variation in and upper limits of nephron endowment. The principal investigator herein has identified that distinct mouse strains can be used to model and dissect the genetic basis of differences in nephron number, as several inbred strains and diversity outbred hybrids exhibit distinct, consistent NN phenotypes. Therefore, this proposal sets forth a strategy to identify and subsequently target genetic loci that modify NN outcomes, leveraging QTL mapping algorithms, sequencing data and known gene expression patterns in renal tissue. Secondarily, on a mechanistic basis, it is unclear whether NN variation arises from altered cessation timing, intrinsic changes in NPC activity, or a combination thereof; cellular energetics and mitochondrial function have been implicated. Thus, this proposal will also investigate a mitochondrial mutant mouse model, which exhibits NN elevated above baseline littermate controls, to identify mechanisms by which nephrogenesis can be enhanced. Collectively, by identifying targets and mechanisms that segregate with either high or low nephron number, this research will contribute to the ability to develop diagnostic screens and interventional treatment strategies for deficient nephrogenesis, respectively. Comprehensively, this research plan will aptly be executed in the fulfillment of a fellowship research training plan aimed at fostering the development of an independent physician-scientist in academic pediatric nephrology.

项目总结与摘要 哺乳动物的肾功能严重依赖于在肾脏过程中产生的肾单位的数量 发展。肾单位是肾脏系统的过滤单位，起源于肾单位祖细胞(Npc)。 在发育中的组织边缘的种群。NPC与周围的输尿管芽(UB)相互作用 间质间隔，平衡自我更新和分化为节段性肾单位结构 间充质向上皮间充质转化。因此，肾单位的捐赠是由数量决定的结果。 通过几个过程，包括UB分支和NPC动力学。哺乳动物肾脏的两个值得注意的方面 发育情况如下：(1)不同来源的人肾之间的肾单位数(NN)相差10倍。 个人，每个肾脏从200,000到250万个单位不等；(2)剩余肾同时耗尽 小鼠出生后第3天的祖细胞(人类妊娠34-37周)。这些事实提出了令人信服的研究 问题，因为基因对肾脏器官发生的这些方面的贡献目前尚不清楚。从… 从临床的角度来看，低肾单位的捐赠在早产儿队列中特别普遍， 会导致高血压和慢性肾脏疾病(CKD)。这些条件构成了一个巨大的 世界各地的疾病负担，特别是由于出生后没有已知的新一代肾单位。虽然有各种各样的 遗传和围产期因素已被证明可减少NN，但仍有明确的需要确定遗传 对肾单位捐赠的变化和上限的贡献。这里的首席调查员有 确定了不同的小鼠品系可以用来模拟和剖析肾单位差异的遗传基础 数量，因为几个近交系和多样性近交系杂交种表现出明显的、一致的NN表型。 因此，这项建议提出了一种策略，以识别并随后针对修改NN的遗传基因座 结果，利用QTL定位算法、测序数据和已知的肾脏基因表达模式 组织。其次，在机械论的基础上，还不清楚神经网络的变异是否是由改变的停止引起的 时间，鼻咽癌活动的内在变化，或其组合；细胞能量学和线粒体功能 都有牵连。因此，这项提议还将研究线粒体突变小鼠模型，该模型 显示NN高于基线窝产仔对照组，以确定肾脏发生的机制 增强版。总的来说，通过确定与高或低肾单位分离的靶点和机制 数字，这项研究将有助于开发诊断筛查和介入治疗的能力 肾虚生肾的治疗策略。 综上所述，这项研究计划将在完成研究员研究培训计划的过程中适当地执行 旨在促进儿科肾病学术领域独立内科科学家的发展。